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Combinatorial Therapies for Infantile Neuronal Ceroid Lipofuscinosis

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Presentation on theme: "Combinatorial Therapies for Infantile Neuronal Ceroid Lipofuscinosis"— Presentation transcript:

1 Combinatorial Therapies for Infantile Neuronal Ceroid Lipofuscinosis
Mark S. Sands, Ph.D. Washington University School of Medicine

2 Infantile Neuronal Ceroid Lipofuscinosis (Infantile Batten Disease)
- Palmitoyl protein thioesterase 1 (PPT1)-deficient - Accumulation of autofluorescent material - Retinal degeneration/visual deficits - Severe brain atrophy - Seizures - Mouse model PPT1-deficient Neurodegeneration Brain atrophy, seizures *Simple monogenic disease but complex biochemical, histological, and clinical phenotype

3 Treatment of INCL Single Therapies for INCL are ineffective
or only partially effective -CNS-directed gene therapy -Neuronal stem cells -Enzyme replacement -Small molecule drugs Phosphocysteamine Resveratrol -Bone marrow transplantation

4 CNS-Directed AAV-Mediated Gene Therapy
& Phosphocysteamine

5 Rationale AAV2/5-mediated gene therapy
-supplies enzyme to localized regions of CNS Phosphocysteamine -cleaves thioester linkages in palmitoylated proteins in regions with low PPT1 activity

6 Combination Therapy (AAV2/5 and PC)
IP Phosphocyst. (Daily, 60mg/kg) Analyses (Life span, etc.) IC AAV2/5 PND2 PND28

7 Survival & Motor Function
Life Span AAA/BMT (~130d) Twi AAV (~40d) (~70d) (≈70 d) Rocking Rotarod

8 CNS-Directed AAV-Mediated Gene Therapy
& Minozac (anti-inflammatory)

9 Rationale AAV2/5-mediated gene therapy
-supplies enzyme to localized regions of CNS Minozac -decreases CNS inflammation

10 Combination Therapy (AAV2/5 and Minozac)
IP Minozac (Daily, 2.5mg/kg) Analyses (Life span, etc.) IC AAV2/5 PND2 PND28

11 Survival & Motor Function

12 CNS-Directed AAV-Mediated Gene Therapy & Bone Marrow Transplantation

13 Rationale AAV2/5-mediated gene therapy
-supplies enzyme to localized regions of CNS Bone Marrow Transplantation -supplies additional enzyme to CNS? -decreases CNS inflammation?

14 Combination Therapy (AAV2/5 and BMT)
400rads radiation i.v. injection of GFP+ BM cells Analyses (Life span, etc.) Genotype PND2 PND3 PND4 IC injection of PPT1-AAV2/5

15 Increased survival in AAV+BMT mice
12 mo 18 mo 8 mo Macauley et al, under review JCI

16 Improved Motor Function (Rotorod)
Age (months) Macauley et al, under review JCI

17 Increased PPT1 Activity Following BMT

18 Increased AAV Genomes Following BMT

19 Histological improvement following AAV+BMT
18 mo 8 mo 8 mo 12 mo 18 mo * * Macauley et al, under review JCI

20 Conclusions AAV2/5-PPT1 provides the single greatest benefit
AAV2/5-mediated gene therapy + Phosphocysteamine: - Phosphocysteamine alone provides essentially no benefit - AAV2/5-PPT1 + PC minimally improves motor function AAV2/5 + Minozac: - Minozac alone provides essentially no benefit - AAV2/5-PPT1 + Minozac improves survival and motor function AAV2/5-mediated gene therapy + BMT: - BMT alone provides no benefit - AAV2/5-PPT1 synergizes with BMT to dramatically increase lifespan and improve motor function.

21 Acknowledgements Sands Lab: Northwestern University Shannon Macauley
Marie Roberts Josh Woloszynek Adarsh Reddy Kevin O’Dell Sarah Hohm Elizabeth Qin Jacqui Hawkins Tom Daly Darshong Lin Anthony Frisella Northwestern University Martin Watterson King’s College - London Catherine Kielar Andrew Wong Jonathon Cooper Yewande Awoboh-Pearse Support NIH - NS43205 & HD55461 NRSA Fellowship F31 NS056718 BDSRA Postdoctoral Fellowship Hunter’s Hope Legacy of Angels Foundation Tay-Sachs and Allied Diseases

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